Vitamin D requirements and supplementation during pregnancy

Abstract

Purpose of review

The topic of vitamin D supplementation during pregnancy is very controversial. This review attempts to provide balanced knowledge with respect to this topic gained in the past 18 months.

Recent findings

Two recent reports, one by the Institute of Medicine, and one by The Endocrine Society are greatly divergent with respect to the nutritional requirement for vitamin D, as well as, the level of circulating 25-hydroxyvitamin D that is desirable. These recommendations will be discussed along with recent observational data and a recently completed randomized controlled trial dealing with vitamin D requirements during pregnancy.

Summary

Current evidence supports the concept that circulating 25-hydroxyvitamin D should be 40–60 ng/ml (100–150 nmol) during pregnancy and a daily intake of 4000 IU vitamin D₃ is required to attain that circulating level.

Introduction

The function and requirement of vitamin D during pregnancy for both mother and fetus has remained a mystery. This fact was highlighted by The Cochran Review in 1999 that reported a lack of randomized controlled trials (RCTs) with respect to vitamin D requirements during pregnancy [1]. Unfortunately, during the past decade no new RCT data has been published to further the information from the 1999 Cochran Review. This lack of information about vitamin D and pregnancy is further evidenced by the recent recommendations released by the Institute of Medicine (IOM) [2^•], which are really no different than the recommendations they released in 1997 [3].

The current dietary recommendation for vitamin D during pregnancy remains archaic for a simple reason, fear of vitamin D toxicity [4^••]. It is important to look at the history here. In 1947, Dr E. Obermer [5] presented evidence that pregnant women required several thousand IUs of vitamin D daily during pregnancy. This recommendation had barely seen ‘the light of day’ before vitamin D was erroneously associated with causing supravalvular aortic stenosis syndrome during pregnancy [4^••,6]. Thus, vitamin D was basically viewed as poison to the pregnant woman and the medical profession adhered to the largely useless 200 IU/day recommendation for adults put forth by the Forbes committee in 1963 [7]. At present, this absurdly low recommendation largely remains in force, although a recent recommendation by The Endocrine Society may supply a positive impact at increasing it [8^••].

What constitutes vitamin D deficiency during pregnancy?

What circulating level of 25-hydroxyvitamin D [25(OH)D] does a pregnant woman require to be considered replete? The 2010 IOM report states that if one exhibits a circulating 25(OH)D level of 20 ng/ml (50 nmol) that individual should be considered replete [2^•]. That document also stated that individuals consuming an adequate diet would receive enough vitamin D from that diet without consideration for race, latitude, or season, and not require a dietary supplement. These statements from the IOM should preclude anyone from taking their document or recommendations from it seriously. Fortunately, new clinical guidelines have recently been released by The Endocrine Society that provides serious guidance to the vitamin D deficiency problem [8^••]. Let us compare the two report recommendations for vitamin D with respect to pregnancy. As mentioned earlier, the IOM recommended a circulating level of 25(OH)D to be 20 ng/ml (50 nmol), whereas The Endocrine Society recommends a level of more than 30 ng/ml (>75 nmol) [2^•,8^••]. To achieve the 20 ng/ml, the IOM recommends a daily vitamin D of 400–600 IU/day, which they state can be obtained through dietary means without supplementation [2^•]. In contrast, The Endocrine Society recommends an intake of 1500–2000 IU/day to achieve a circulating 25(OH)D level of more than 30 ng/ml [8^••]. How could these recommendations be so divergent? The IOM chose only to use RCT data limited to skeletal integrity, whereas The Endocrine Society chose to use a combination of peer-reviewed basic and clinical scientific publications [2^•,8^••]. The reader will have to decide which report is best to adopt and use for patient guidance.

To examine the actual vitamin D deficiency rates during pregnancy, two recent publications provide some important insight. Hamilton et al. [9^•] and Johnson et al. [10] both provide shocking deficiency rates during pregnancy in a sunny climate even using the recent IOM normative 25(OH)D range of 20 ng/ml [2^•]. This deficiency problem is especially severe in the minority populations [9^•,10]. The IOM report claims that individuals obtain enough vitamin D from their diet to achieve the circulating 25(OH)D level minimum of 20 ng/ml. This statement is in direct conflict with two recent supplementation studies during pregnancy that failed to achieve this minimum circulating requirement for 25(OH)D [11,12].

Consequences of vitamin D deficiency during pregnancy

There are many possible consequences of vitamin D deficiency during pregnancy that can contribute to increased morbidity and mortality of both mother and infant.

Calcium homeostasis and skeletal integrity

At the top of any list concerning vitamin D deficiency, calcium homeostasis and skeletal integrity remain a top priority. What is really surprising is the relative dearth of information that exists between this topic and its effect on the pregnant woman and her fetus. There is no RCT data to guide us here and, thus, we must rely on observational data. A superb observational study by Yorifuji et al. [13] provides data to suggest that craniotabes in the newborn infants is the earliest sign of subclinical vitamin D deficiency during pregnancy. At 1 month of age, infants with craniotabes had significantly higher serum alkaline phosphatase, intact parathyroid hormone and lower circulating 25(OH)D levels than infants not exhibiting craniotabes. Several other recent observational studies have linked poor nutritional vitamin D status to abnormalities in both the maternal and fetal skeletal markers and skeletal integrity itself [14-17]. It is also worth mentioning an animal model paper that suggests pregnancy itself upregulates intestinal calcium absorption and skeletal mineralization independently of vitamin D suggesting that vitamin D is not required for the skeletal adaptations during pregnancy [18]. However, this study was performed in mice and its relevance to human physiology remains to be established.

Complications of pregnancy

Complications of pregnancy include pre-eclampsia, gestational diabetes and hypertension. Although these complications of pregnancy are well known and contribute to morbidity and mortality during pregnancy, their association to nutritional vitamin D status is a new area of investigation. Again, we have no RCT data to guide us here, only observational studies.

Bodnar et al. [19] first described the relationship between poor vitamin D status and risk of pre-eclampsia. Three additional observational studies have strengthened this observation in the past year. Baker et al. [20], using a nested case–control study found that maternal midgestation vitamin D deficiency was associated with increased risk of severe pre-eclampsia. Robinson et al. [21^•], utilizing a case–control investigation with gestation-matched contemporaneous control participants, determined that circulating 25(OH)D levels were significantly decreased in early-onset severe pre-eclampsia (EOSPE) individuals. This group has further demonstrated that 25(OH)D levels are lower among patients who are small-for-gestational-age (SGA) in EOSPE than those infants without growth retardation [22]. It was concluded from this study that vitamin D status may impact fetal growth through placental mechanisms. Along the spectrum of hypertensive disorders of pregnancy, additional evidence of vitamin D’s role during pregnancy comes from an observational study by Ringrose et al. [23], who found a high prevalence of vitamin D deficiency in pregnant women in Canada and that this deficiency was independently linked to hypertension in these women that may be regulated by flow-mediated dilation [24^••].

A recent observational study by Lau et al. has provided us with a link between low vitamin D levels and gestational diabetes mellitus [25]. Lau et al. [25] found that circulating 25(OH)D levels were inversely associated with fasting, 2-h blood glucose levels during glucose tolerance testing and glycated hemoglobin levels (HbA1c). Multivariate analysis identified 25(OH)D and glucose levels as independent predictors of HbA1c. Thus, low 25(OH)D levels are associated with poor glycemic control during pregnancy.

Alterations in immune function

The control of immune function, both adaptive and innate, by nutritional vitamin D status is a very active area of investigation with regard to pregnancy. Liu et al. [26], using the mouse as an experimental animal for assessing vitamin D’s role in the regulation of placental inflammation, have determined that maternal and fetal vitamin D levels play a pivotal role in controlling placental inflammation. Does vitamin D play a similar role in human pregnancy? Current data would suggest that it does. Walker et al. [27^••] have shown that cord blood vitamin D status in human participants control the innate immune response. This study demonstrated that cord blood vitamin D deficiency, by its effect on toll-like receptor-induced antimicrobial production, altered in-vitro monocyte responses [27^••]. The result of this defect would be decreased barrier protection against invading pathogens. Actual observational data suggest that this is, in fact, the case.

Belderbos et al. [28^•] have demonstrated that nutritional vitamin D deficiency in otherwise healthy neonates is associated with increased risk of respiratory syncytial viral bronchiolitis. Further, maternal vitamin D deficiency is associated with bacterial vaginosis and this deficiency may contribute to the strong racial disparity in the prevalence of bacterial vaginosis [29,30]. Similar mechanisms, with respect to vitamin D deficiency and innate immune function, likely contribute to periodontal disease during pregnancy [31]. Low circulating 25(OH)D levels have also been linked to the risk of respiratory infection, wheezing and asthma [32-34] and have an apparent impact on the markers of severity of childhood asthma [35] possibly by altering T-regulatory cells [36].

Finally, one of the most important aspects of vitamin D’s proposed interactions with the adaptive immune system involves its potential to alter multiple sclerosis susceptibility of the infant later in life by improving nutritional vitamin D status during pregnancy [37-39].

Pregnancy outcomes

The relationship between circulating 25(OH)D and pregnancy outcomes remains a limited field of investigation because of a lack of RCT’s. However, recent observational studies have linked vitamin D deficiency to an increase in primary cesarean section [40] and premature delivery [41]. Further, vitamin D deficiency during pregnancy has also been linked to an increase in incidence of SGA births [42], as well as, a higher risk of schizophrenia [43]. This is an area of research that will require more investigation.

Determining the vitamin D requirement during pregnancy

Twelve years ago The Cochran Database of Systematic Reviews published a document that stated ‘with the publications to that point, no recommendations with respect to vitamin D requirements during pregnancy could be made’ [1]. This publication prompted our group to obtain NIH funding along with a US Food and Drug Administration (FDA) investigational drug number (#66 346) and perform a multiyear RCT to determine what was the nutritional vitamin D requirement during pregnancy, actually. This RCT, which was in reality a phase I FDA trial, has recently been published [4^••]. Briefly, we hypothesized that 4000 IU/day vitamin D₃ would be more efficacious and effective than the standard dosing regimen of 400 IU/day in achieving a circulating 25(OH)D level of more than 32 ng/ml (80 nmol) in the pregnant woman without causing any safety concerns. From the results of our study, we concluded that pregnant women require a total vitamin D intake of 4000 IU/day based on attainment of optimal circulating 25(OH)D levels that supported maximal circulating levels of 1,25-hydroxyvitamin D [1,25(OH)₂D], optimization of intestinal calcium absorption and urinary excretion and suppression of secondary hyperparathyroidism. It is also important to note that we did not observe a single adverse event that could be attributed to these levels of vitamin D supplementation. It is also important to compare our study results with respect to two recent reports dealing with vitamin D supplementation during pregnancy [2^•,8^••]. The IOM report recommends a vitamin D intake of 400–600 IU/day and states that this level can be obtained solely from the diet. Further, this intake level would be sufficient to meet their circulating 25(OH)D target of 20 ng/ml (50 nmol/l) [2^•]. Even using this conservative 25(OH)D level, their recommendation would have left more than 50% of our total cohort and more than 80% of African–American women in the cohort deficient at study entry [10]. The Endocrine Society’s recommendation of a daily vitamin D intake of 1500–2000IU and target 25(OH)D level of more than 30 ng/ml (75 nmol/l) is more sound advice, yet is still conservative when compared with our study results. It must be pointed out that the purpose of the IOM report was to guide food manufacturers and fortifiers and is not intended to guide clinical practice [2^•]. On the contrary, clinical practice guidance is precisely the purpose of The Endocrine Society’s recommendations [8^••]. Unfortunately, however, the American College of Obstetrics and Gynecologists (ACOG) have chosen the food fortification document as a clinical guide as opposed to The Endocrine Society’s true clinical guidelines document [44]. This ACOG document states that ‘vitamin D screening and supplementation during pregnancy is not required ‘unless’ women live in cold climates, reside in northern latitudes, wear sunscreen and protective clothing, are ethnic minorities, or are vegetarians’ [44]. This ‘unless group’ basically defines the entire north American population and confirms the data from our RCT, conducted in a subtropical climate, that describes rampant vitamin D deficiency in this US population during pregnancy [4^••,9^•,10].

Conclusion

Maintaining physiologically adequate circulating levels of 25(OH)D, through substantial oral supplementation of vitamin D, is potentially very beneficial in multiple health outcomes with essentially no risk of side-effects during pregnancy. The reader is advised to read and synthesize the evidence and formulate his or her own opinions and practices, and not blindly rely on reports from ‘expert’ panels with unknown agendas. Current RCT data suggest that a daily intake of 4000 IU/day vitamin D₃ is required to normalize vitamin D metabolism in the pregnant women [4^••].

Key points.

• The new Institute of Medicine recommendations with regard to pregnancy and vitamin D are woefully inadequate.

• The recent Endocrine Society recommendations with regard to pregnancy are conservative but realistic with regard to recent data.

• Vitamin D deficiency during pregnancy is a major concern and in all likelihood contributes to the complications of pregnancy as well as unfavorable outcomes in the infant later in life.

• New randomized controlled trial data reveal that a daily intake of 4000 IU/day vitamin D₃ is required to meet the requirement in all pregnant women without any safety concerns.